Personalized, Patient-Centered Strategies Shape the Evolving Management of Metastatic Pancreatic Cancer

The management of metastatic pancreatic cancer continues to evolve with an increasing focus on personalization—both biologically and holistically, according to Efrat Dotan, MD, who emphasized that when patients first present with metastatic disease, treatment discussions must extend beyond tumor biology to encompass comorbidities, performance status, nutrition, and patient goals to guide individualized care decisions.

“[We have to consider that] treatment for metastatic pancreatic cancer is very tough,” Dotan said. “It is not just about the chemotherapy and the treatment, but [rather something] broader than that.”

In an interview with OncLive®, Dotan discussed patient- and disease-related factors that help drive frontline treatment decision-making for patients with metastatic pancreatic cancer, underscoring the need to address patient goals when mapping out therapy.

She also spoke about the integration of NALIRIFOX (irinotecan liposome [Onivyde] with oxaliplatin, 5-fluorouracil [5-FU], and leucovorin) into the frontline treatment paradigm following the February 2024 FDA approval of the regimen, based on data from the phase 3 NAPOLI 3 trial (NCT04083235).1 Additionally, Dotan outlined findings from the phase 2 GIANT trial (NCT04233866), which evaluated dose-reduced chemotherapy in older, frail patients with metastatic pancreatic cancer. Although this population experienced a median overall survival (OS) of 4.7 months (95% CI, 4.1-7.4) with modified gemcitabine plus nab-paclitaxel (Abraxane) vs 4.4 months (95% CI, 3.1-8.9) with dose-reduced 5-FU and liposomal irinotecan, patients between both arms who received at least 2 doses of treatment achieved a median OS of 8.0 months (95% CI, 5.9-10.0).2

Dotan is executive medical director of the Ann B. Barshinger Cancer Institute, Cancer Services, and Cancer Research, as well as the chairperson of the Cancer Committee at Penn Medicine Lancaster General Health.

OncLive: When a patient is newly diagnosed with metastatic pancreatic cancer, what key goals guide your initial discussions regarding treatment planning?

Dotan: [When] these patients present, it’s a shocking diagnosis. People know how challenging pancreatic cancer is, how aggressive the disease is, and there’s a lot of fear and concern. The first meeting is a time to get a sense of the patient’s overall health, the patient’s goals, values, [and] support system. [We] assess how are they coming into this disease and try to get a sense of what the best approach would be for that patient.

We talk a lot about personalizing therapy and precision oncology, but in pancreatic cancer, it is critical that we think of the patient holistically and try to understand how to personalize therapy, not just to the biomarkers and the molecular changes, but also to the patient who is sitting in front of us—thinking about their goals, values, preferences, support system, and ability to go through therapy.

What are some of the key factors you typically discuss with patients that can ultimately influence the treatment decisions made in the metastatic setting?

Understanding the patient’s other comorbidities, functional status, and fitness [is critical]. Many patients with pancreatic cancer, regardless of age, can present with a lot of nutritional deficits [that affect] their performance status. [For example], if they have extensive liver involvement or significant biliary blockage, all those things can affect their ability to tolerate therapy.

Understanding holistically all these other factors that are related to the cancer—but not the cancer itself—is critical when deciding on treatment.

Then, more than that, we need to [consider] the patient’s overall function, how they’re functioning at home, and how active they are. There’s a big difference between somebody who shows up and is still active, [perhaps] not working but getting out and doing things, vs patients who are debilitated by pain or by difficulty [maintaining] their nutritional needs, and those [who] spend more than 50% of [their] time in bed. All those factors [help] clearly direct us toward the appropriate treatment recommendation.

How has the FDA approval of NALIRIFOX influenced the current treatment paradigm for patients with metastatic pancreatic cancer, particularly in terms of first-line therapy selection?

The adoption of NALIRIFOX has been slow in pancreatic cancer. Let me start by saying that [NAPOLI 3] was a very important trial. It’s important because it clearly demonstrated the superiority of a triple-drug regimen over gemcitabine and nab-paclitaxel. Before the study was published, we all thought, ‘Oh, there’s not a huge difference—maybe gemcitabine/nab-paclitaxel can be used for patients who don’t want a port or a pump.’ However, the trial actually showed that there was a benefit to giving triple-drug therapy up-front compared with gemcitabine/nab-paclitaxel. The data that came out of this study are very valuable.

The challenge, however, is that at the end of the day, the outcomes were very similar to those seen with FOLFIRINOX. Is it worth giving a patient NALIRIFOX instead of FOLFIRINOX, especially considering the cost of liposomal irinotecan and the comparable outcomes?

Physicians are already comfortable with FOLFIRINOX. They know how to use it, manage toxicities, and modify doses. So why change practice? There are two important pieces in the NALIRIFOX data. One is that the oxaliplatin dose was lower in the study, which is important, especially when treating patients who already have neuropathy or are older and at higher risk for developing neuropathy. That lower dose might allow patients to stay on treatment longer.

The other point is that [NAPOLI 3] enrolled more older patients compared with the original FOLFIRINOX trial, providing some proof of concept for treating older patients with this regimen. That said, many of us who treat pancreatic cancer and see older patients—since it’s a disease that affects older individuals—have already become accustomed to modifying and treating older adults with triple-drug therapy.

[NAPOLI 3] added important data, but I don’t believe NALIRIFOX has been widely incorporated into practice—at least not to the extent it would have been if the data had shown a significantly greater OS benefit.

How do you view clinical trial enrollment as a treatment option for patients with metastatic pancreatic cancer, and why is expanding access to trials so critical for advancing therapy development in this population?

[Clinical trials] are the way to [expand] our treatment arsenal and move the needle forward. There’s a lot of excitement around new trials in pancreatic cancer—especially the new RAS inhibitors that are coming down the pipeline—and some other new targets that are quite exciting. [There are also] additional studies looking at drugs affecting cachexia, which is such a critical part of what patients with pancreatic cancer experience.

If I have a trial [available], I urge patients to join. If I have a patient who I think is very fit, interested in a trial, and willing to travel, I will do my best to find a study for them. The challenge with enrollment in clinical trials for patients with pancreatic cancer is that this is a really tough disease. To be able to travel to a distant site to participate in a trial when you have pancreatic cancer, a lot of things need to fall into place to make that happen—and many patients will struggle with that.

That’s a big challenge and why it’s important to open these trials as widely as possible—to try to get them opened in community sites where patients can get access. Then, I think enrollment will be better. If you bring the study to the patient, it becomes much easier to encourage participation.

What were the key takeaways and clinical implications from the preliminary analysis of the GIANT study?

We’re still waiting for the final analysis, but the preliminary results showed poor outcomes for patients who are very vulnerable and may not be able to tolerate chemotherapy. Identifying those patients and personalizing treatment to the individual sitting in front of you is critical in this disease.

The GIANT study was an important trial because it addressed a population that hasn’t been studied before. These were older, more frail patients [who were more representative of who] we see in clinic—and we all see them because pancreatic cancer is a disease of older adults. The study enrolled patients over the age of 70, and they had to have geriatric vulnerabilities to enroll. Patients were randomly assigned to receive dose-reduced therapy with gemcitabine and nab-paclitaxel given every other week, or 5-FU and liposomal irinotecan, also given every other week.

The study showed no difference in outcomes between both groups. Survival was quite poor [with a median OS of] less than 5 months for each arm. Toxicity was similar overall, although the regimens had different profiles: gemcitabine and nab-paclitaxel were associated with more neuropathy, while 5-FU and liposomal irinotecan caused more diarrhea. Overall, grade 3 toxicity rates were about the same.

What was really striking, in my opinion, was that patients who were able to tolerate more than two doses—the [72% of patients between both arms] who stayed on treatment for more than 1 month—had a median OS of 8.0 months. That’s comparable to what we would expect with standard-dose gemcitabine and nab-paclitaxel. Therefore, we could attenuate doses, give less treatment, and still achieve the same outcomes as with full-dose chemotherapy.

The big question is how to identify those patients. That’s the second significant finding from this trial: there were key baseline criteria related to nutrition, functional status, and quality of life that clearly predicted outcomes. Patients with better baseline quality of life and nutrition had significantly better outcomes when treated. Again, this brings me back to the point I mentioned earlier—personalization of therapy. Not everyone is a candidate for treatment or will benefit from it. We need to do a better job identifying those factors up-front and having those discussions with patients to ensure we are truly personalizing therapy and providing the best treatment for each individual.

What is your main takeaway message for colleagues when it comes to approaching treatment discussions and decision-making for patients presenting with metastatic pancreatic cancer?

It’s important to think about personalizing therapy in two ways. [The first] is biologically—every patient with metastatic pancreatic cancer should have molecular testing. That’s very critical, including BRCA testing as recommended by all guidelines, but [we should conduct] next-generation sequencing. It’s rare that we find a target, but if we do, it can make a huge difference. With RAS inhibitors hopefully coming down the pipeline, we need to know the RAS mutation status. If they don’t have a RAS mutation, we need to dig deeper and find what other mutations or drivers are contributing to their cancer. Molecular and biologic personalization—or precision oncology—needs to happen for all of these patients.

On the other hand, personalization to the patient, their needs, core values, preferences, and goals is critical. Thinking about the holistic picture of the patient: What can they tolerate? What will benefit them? Is it worth it for them to go through therapy? For many patients, that may not be the right decision.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed February 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
2. Dotan E, Catalano PJ, Lenchik L, et al. A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer (GIANT): ECOG-ACRIN EA2186. J Clin Oncol. 2024;42(suppl 16):4003. doi:10.1200/JCO.2024.42.16_suppl.4003